Squalene synthetase is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form squalene (Poulter, C. D.; Rilling, H. C., in "Biosynthesis of Isoprenoid Compounds", Vol. I, Chapter 8, pp. 413-441, J. Wiley and Sons, 1981, and references therein). This enzyme is the first committed step of the de novo cholesterol biosynthetic pathway. The selective inhibition of this step should allow the essential pathways to isopentenyl tRNA, ubiquinone, and dolichol to proceed unimpeded. Squalene synthetase along with HMG-CoA reductase have been shown to be down-regulated by receptor mediated LDL uptake (Faust, J. R.; Goldstein, J. L.; Brown, M. S. Proc. Nat. Acad. Sci. U.S.A. 1979, 76, 5018-5022), lending credence to the proposal that, inhibiting squalene synthetase will lead to an up-regulation of LDL receptor levels, as has been demonstrated for HMG-CoA reductase, and thus ultimately should be useful for the treatment and prevention of hypercholesterolemia and atherosclerosis.
U.S. Pat. No. 3,657,282 (Merck) (Division U.S. Pat. No. 3,822,296) discloses antibiotics of the structure ##STR2## wherein R=SO.sub.3 H, SO.sub.2 R*, H, hydrocarbyl other than alkyl (eg. alkenyl, alkynyl, phenyl and naphthyl), substituted hydrocarbyl, CO.sub.2 H, CO.sub.2 R*, SO.sub.3 NR.sub.2, heterocycle*, amino*, OH, OR, SH, SR, CHO, halogen NO.sub.2, CN, PO.sub.3 H.sub.2, AsO.sub.3 H.sub.2, acyl, --CHR.sup.1 R.sup.3 where R.sup.1 =H, Me; R.sup.3 =R as above, preferably at least one R not =H, R preferably contains 1-10 carbons. *=optionally substituted.
Starting materials employed to prepare the above antibiotics include ##STR3## wherein R can be SO.sub.3 H, and X and Y are hydroxy or functional equivalent precursor to epoxide: eg. OH, halo, azide, RCO.sub.2 --, RSO.sub.2 O--, R.sub.2 S.sup.+ --, R.sub.3 N.sup.+ --, ArO--, R.sub.2 PO.sub.2 --, RSO.sub.2 NR.sup.1 --. One of X and Y must be an oxygen radical.
EP 89/0-344-980 (Smith Kline) discloses .alpha.-antagonists of the structure ##STR4## wherein Y or Z may be --SO.sub.2 R, --P(R)O(OR), --PR.sub.2 O, --PO(OR).sub.2, and amides.
WO 88/00061 (Amersham) discloses Technetium-99 complexes for bone scanning having the structure ##STR5## wherein R.sup.1 and R.sup.3 =H, SO.sub.3 H or alkyl substituted with SO.sub.3 H and optionally one or more heteroatoms; R.sup.4 can also be SO.sub.3 H or OH, NH.sub.2, NHMe, NMe.sub.2, lower alkyl substituted with a polar group;
R.sup.2 =same as R.sup.4 except not SO.sub.3 H and n=0, 1. PA1 R.sup.1 =H, alkali metal, Zn, Cd; PA1 R.sup.2 =H, lower alkyl; PA1 r=2, 3; and x, y=1, 2, 3. PA1 n=1 to 4. PA1 D=optionally substituted, saturated or unsaturated aliphatic radical (&lt;40 carbons), can be interrupted by heteroatoms such as O, SO.sub.2, NH, NR. PA1 W=PO.sub.3 R.sub.2, SO.sub.3 R, SO.sub.2 R, --NY--SO.sub.3 R, --SO.sub.2 NR.sub.2, --SSO.sub.3 R, CO.sub.2 R, OH, NR.sub.3.sup.+, NR.sub.2, CONR.sub.2. PA1 R.sup.1, R.sup.2 =C1-C6 alkyl or alkoxy; PA1 R.sup.3 =H, C1-C6 alkyl or alkoxy, C2-C6 alkenyl, alkynyl, alkenyloxy, alkynyloxy; all optionally substituted with one or more halogens; and PA1 R.sup.4 =H, C1-C4 alkyl or physiologically acceptable cation. PA1 R.sup.5a is H, alkyl, arylalkyl or aryl; PA1 R.sup.4 is H, alkyl, cycloalkyl, aryl, arylalkyl, metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester; PA1 Z is H, halogen, lower alkyl or lower alkenyl; PA1 R.sup.1 a lipophilic group containing at least 7 carbons and is alkyl containing 7 to 25 carbons in the chain; alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 double bonds; alkynyl containing 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds; and where in the above groups alkenyl and/or alkynyl may be substituted or unsubstituted; cycloalkyl; cycloheteroalkyl linked through a carbon on the ring or a heteroatom; aryl; heteroaryl; heteroarylalkyl; cycloalkylalkyl; cycloheteroalkylalkyl; or a group of the structure ##STR16## wherein Ar is aryl (such as phenyl or naphthyl), heteroaryl (5 or 6 membered) and may include one to three additional rings fused to Ar (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl) and wherein (CH.sub.2).sub.p contains from 1 to 15 carbons, preferably 2 to 12 carbons, in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and may contain an ether or amino function in the chain, and/or may include 0, 1, 2 or 3 substituents as defined below for R.sup.6 ; and R.sup.6, R.sup.7, R.sup.8 and R.sup.8a are the same or different and are H, alkyl containing 1 to 40 carbons, preferably from 3 to 25 carbons, alkoxy containing 1 to 40 carbons, preferably from 3 to 25 carbons, alkenyl containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkenyloxy containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkynyl containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkynyloxy containing 2 to 40 carbons, preferably from 3 to 25 carbons, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl, cycloalkylalkyl, Ar-alkyl, (such as arylalkyl), ArO (such as aryloxy), Ar-amino (such as arylamino), hydroxy, halogen, nitro, Ar (such as aryl), amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, alkenyl, aryl or any of the Ar groups mentioned above), thiol, alkylthio, Ar-thio (such as arylthio), alkylsulfinyl, Ar-sulfinyl (such as arylsulfinyl), alkylsulfonyl, Ar-sulfonyl (such as arylsulfonyl), carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, Ar-carbonyloxy (such as arylcarbonyloxy), Ar-carbonylamino (such as arylcarbonylamino) or alkylcarbonylamino, as well as any of the Ar groups as defined above, and preferably wherein the total number of carbons in the substituted Ar--(CH.sub.2).sub.p -- group exceeds 10 carbons; including pharmaceutically acceptable salts thereof such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and other FDA approved cations such as ammonium, choline, diethanolamine, ethylenediamine, and salts of naturally occuring amino acids such as arginine, lysine, alanine and the like. PA1 R.sup.3 is H, a metal ion such as Na or K; PA1 R.sup.4 is a metal ion such as Na or K; PA1 R.sup.1 is alkenyl such as ##STR29## wherein (CH.sub.2).sub.x is defined as (CH.sub.2).sub.p above and x is preferably 2 to 8, ##STR30## 20 m is 1 to 5; ##STR31## n=1 to 15; R.sup.11, R.sup.11a, R.sup.11b, and R.sup.11c are independently selected from H, alkyl such as propyl, alkoxy, such as methoxy or propyloxy, alkenyl such as ##STR32## wherein R.sup.12, R.sup.12a and R.sup.12b are independently selected from H, aryl (such as phenyl or naphthyl), alkylphenyl (such as p-propylphenyl, p-pentylphenyl), alkyl containing 1 to 20 carbons (such as p-heptyl), halo, alkoxy (such as methoxy or propyloxy), alkenyl (such as ##STR33## arylalkyloxy (such as phenethyloxy), alkenyloxy (such as ##STR34## aryloxy (such as phenoxy), phenylalkyl (such as benzyl, phenylpropyl), alkylphenoxy (such as orthobutylphenoxy), alkenylphenyl (such as ##STR35## wherein R.sup.14 is aryl, heteroaryl, aryloxy, heteroaryloxy, cycloalkyl, heterocycloalkyl, and (CH.sub.2).sub.p' and (CH.sub.2).sub.p" are as defined above for --(CH.sub.2).sub.p --. Preferred p' and p" are independently 1 to 4; EQU Ar.sup.1 --O--Ar.sup.2 --(CH.sub.2).sub.p -- PA1 wherein Ar.sup.1 and Ar.sup.2 are independently selected from any of the Ar groups defined hereinbefore, and (CH.sub.2).sub.p is as defined hereinbefore. PA1 R.sup.4 is an alkali metal such as K or Na PA1 Z is H and Prodrug ester is bis(pivaloyloxymethyl) ester.
U.S. Pat. No. 4,032,521 (Merck) discloses inter-mediates, in cephalosporin synthesis, of the structures ##STR6##
WO 90/07513 (Gas Research Institute) discloses electrolytes for fuel cells of the structure ##STR7## wherein R=organic radicals with 1 or more F atoms;
U.S. Pat. No. 4,254,215 (Ciba Geigy AG) discloses a process for photographic developers wherein one component of a developer solution is: EQU HS--D--(W).sub.n
wherein
DE 89/3739691-A (Hoechst) (Derwent #89-173507/24) discloses herbicides and plant growth regulators of the structure ##STR8## wherein Y=CH, N; X=O, S; Z.dbd.CH, N;
New intermediates are disclosed of the structures ##STR9##
Burton, D. J., J. Am. Chem. Soc. 1989, 111, 1773-1776 discloses electrolytes and chelators of the structures EQU (HO).sub.2 P(O)CF.sub.2 SO.sub.3 Na (HO).sub.2 P(O)CF.sub.2 SO.sub.3 H
Su, D.; Cen. W.; Kirchmeier, R. L.; Shreeve, J. M., Can. J. Chem. 1989, 67, 1795-1799, disclose electrolytes and chelators of the structures ##STR10##
Farrington, G. K.; Kumar, A.; Wedler, F. C., J. Med. Chem. 1985, 28, 1668-1673 discloses compound 10 as an inhibitor of aspartate transcarbamylase. Compound 24 is a synthetic intermediate. ##STR11##
Musicki, B.; Widlanski, T. S. Tetrahedron Lett.1991, 32, 1267-1270 discloses compound 4 as a synthetic intermediate. ##STR12##
Carretero, J. C.; Demillequand, M.; Ghosez, L., Tetrahedron 1987, 43, 5125-5134 discloses ##STR13## for use in the synthesis of vinyl phosphonates via a Horner-Emmons reaction.
Callahan, L.; Ng, K.; Geller, D. H.; Agarwal, K.; Schwartz, N. B., Analytical Biochemistry 1989, 177, 67-71 discloses an analog of ADP (adenosine diphosphate) of the structure ##STR14##